tbuckley/cabot-search huggingface dataset:
Abstract 4840: Dysregulation of mitochondrial function by PLK1-mediated PDHA1 phosphorylation promotes Cr(VI)-associated lung cancer progression
Authors: Qiongsi Zhang, Zhiguo Li, Xiongjian Rao, Derek B. Allison, Qi Qiao, Zhuangzhuang Zhang, Yifan Kong, Ruixin Wang, Teresa W. Fan, Richard M. Higashi, Andrew N. Lane, Xiaoqi Liu
Journal: Cancer Research (2023)

Abstract Hexavalent chromium (Cr(VI)), an class I environmental carcinogen, not only induces lung epithelial cell transformation but also promotes lung cancer progression by alterations of the cell cycle and cellular energy metabolism. Using Cr(VI)-transformed (CrT) bronchial epithelial cells (BEAS-2B) and parental BEAS-2B cells, we demonstrate that the level of polo-like kinase 1 (PLK1) is highly upregulated in CrT cells, which blocks mitochondrial function, and further promotes cell proliferation both in vitro and in vivo. Cells expressing a high level of PLK1 exhibited repressed mitochondrial activity due to defective modulation of pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1), which facilitates the carbon influx to TCA cycle via catalyzing pyruvate/Acetyl-CoA conversion. Mechanistically, we show that PDHA1 can be directly phosphorylated by PLK1 at T57, which triggers collapse of E1 and PDHA1 degradation via activation of mitophagy. These defects resulted in the inhibition of oxidative phosphorylation and reduction of mitochondrial reactive oxygen species (ROS) generation, eventually inhibiting mitochondrial-mediated apoptotic response. Defining the role of PLK1 in metabolic reprogramming in Cr(VI)-associated cancer progression may give us a new perspective and a target to inhibit Cr(VI)-induced cancer development. In addition, PLK1 inhibitors may be used to increase the chemo-sensitivity of cancer cells by restoring the normal function of mitochondria, thus alleviating the drug resistance caused by dysfunction and hyperpolarization of mitochondria. Citation Format: Qiongsi Zhang, Zhiguo Li, Xiongjian Rao, Derek B. Allison, Qi Qiao, Zhuangzhuang Zhang, Yifan Kong, Ruixin Wang, Teresa W. Fan, Richard M. Higashi, Andrew N. Lane, Xiaoqi Liu. Dysregulation of mitochondrial function by PLK1-mediated PDHA1 phosphorylation promotes Cr(VI)-associated lung cancer progression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4840.
Abstract 4180: Knowledge and barriers to colorectal cancer screenings in people experiencing homelessness in Central Florida
Authors: Harini Sankar, Cassie L. Odahowski
Journal: Cancer Research (2023)

Abstract Purpose of the study: The purpose of this study is to assess how existing knowledge about colorectal cancer screenings and access to resources affect the ability to obtain colorectal cancer screening in people experiencing homelessness in Central Florida. Procedures: A team of researchers from the University of Central Florida will survey subjects who do not have stable housing in two Central Florida locations: a local shelter for men, women, and children and a resource center for the unsheltered. The survey will take place in February 2023 with a sample size goal of 400. The survey will assess current understanding of CRC screenings and available/lacking resources necessary for completing CRC screening in this population. Our inclusion criteria include those who are undomiciled, age 45 and over who speak Spanish or English. Preliminary Results: Anticipated results from previous work by our research team with this population indicate that we will have a large, diverse study sample. The results will include demographic data, frequency of insurance coverage, type of insurance coverage, knowledge of CRC screening recommendations, concerns related to CRC, rate of past completed screening, and perceived barriers to accessing CRC screening. Conclusions: This study will be the first to examine this research topic in Florida. The results will identify the knowledge of CRC screening recommendations, barriers to CRC screening and identify resources needed for the unhoused population to achieve CRC screening in the future. Citation Format: Harini Sankar, Cassie L. Odahowski. Knowledge and barriers to colorectal cancer screenings in people experiencing homelessness in Central Florida. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4180.
Abstract 3416: Suppression of AXL inhibits tumor growth through promotion of dendritic cell migration in lung cancer
Authors: Da-Som Kim, Cha Won Lee, Kyungtaek Im, Yun Jung Choi, Dong Ha Kim, Chang-Min Choi, Wonjun Ji, Jae Cheol Lee, Jin Kyung Rho
Journal: Cancer Research (2023)

Abstract AXL is a receptor tyrosine kinase (RTK) that has a various role in tumor progression such as proliferation, metastasis, angiogenesis, drug resistance and immune tolerance. Although targeting AXL exhibits an anti-cancer effects partially depending on the immune system, their molecular mechanisms have not been fully elucidated. To search the roles of AXL in immune tolerance of tumor, we generated AXL knockout (KO) mice. These AXL KO mice showed the reduced tumor growth in syngeneic LLC-1 model compared to wild type mice. To validate the mechanisms underlying the inhibition of AXL KO-derived tumor growth, we examined tumor-infiltrating lymphocytes (TIL). Compared with tumor-bearing wild type mouse, CD45-positive cells were significantly enhanced in tumor-bearing AXL KO mouse. Especially, these results were dominant in CD8-positive cells and dendritic cells (DCs). Tumor-infiltrating DCs showed the reduction of PD-L1 and Tim3 expression. In addition, the inhibition of AXL led to induce the DCs migration. In conclusion, our data demonstrated that targeting AXL may inhibit tumor growth through the activation of DCs including the enhancement of migration and reduced expression of immune check point proteins. Citation Format: Da-Som Kim, Cha Won Lee, Kyungtaek Im, Yun Jung Choi, Dong Ha Kim, Chang-Min Choi, Wonjun Ji, Jae Cheol Lee, Jin Kyung Rho. Suppression of AXL inhibits tumor growth through promotion of dendritic cell migration in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3416.
Abstract 2333: Verteporfin demonstrates antitumoral effect in murine cholangiocarcinoma models
Authors: Jihye Lee, Xin Wang, Jing Bian, Maggie Cam, Changqing Xie
Journal: Cancer Research (2023)

Abstract Cholangiocarcinoma (CCA) is a heterogenous malignancy that is derived from the biliary epithelium. There is growing concern as CCA incidence in United States has steadily increased. Additionally, CCA disproportionately affects different populations, and overall prognosis remains poor with a 5-year survival rate of 10%. Moreover, the Hippo/yes-associated protein (YAP) pathway has been reported to affect various aspects of tumorigenesis and recent reports showed that higher expression of YAP is negatively associated with the survival rate in CCA patients. Thus, we investigated the antitumoral effect of verteporfin, a YAP pathway inhibitor, in YAP/Akt and Notch/Akt hydrodynamic tail vein injected murine models. Our results demonstrated reduced liver weight in verteporfin treated groups compared to the vehicle treated group. Single cell RNA sequence analysis noted the verteporfin treated group had reduced stemness-related expressing cells in the malignant cell population. Furthermore, B cell, CD8+ T cell, and Tumor-Associated Macrophages M1 (TAM M1) populations increased following verteporfin treatment. In summary, this study indicates that verteporfin reduces tumorigenesis in CCA by the regulation of cancer stemness and modulation of immune cells, which includes anti-tumoral/pro-inflammatory TAM M1 in CCA animal models. Citation Format: Jihye Lee, Xin Wang, Jing Bian, Maggie Cam, Changqing Xie. Verteporfin demonstrates antitumoral effect in murine cholangiocarcinoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2333.
Abstract SY04-01: Understanding and targeting RNA splicing in breast cancer
Authors: Olga A. Anczukow
Journal: Cancer Research (2023)

Abstract Upregulation of SR proteins, a family of 14 essential splicing factors (SFs), often occurs in solid tumors, including in breast, and promotes mammary cell transformation and metastasis in breast cancer models. SR protein alterations often occur without genomic copy number changes, suggesting misregulation at the transcriptional or post-transcriptional levels; however the underlying molecular mechanisms are incompletely understood. Here we investigate the transcriptional and post-transcriptional regulatory mechanisms that control SF-levels in normal mammary cells and their misregulation in cancer cells. We demonstrate the MYC oncogene directly regulates a network of splicing factors that are co-expressed in tumors and act together to regulate their downstream targets and promote cell invasion. In parallel, our work reveals the role of non-coding ‘poison exon’ in regulating SR proteins levels during cell differentiation and in tumors. We uncover an extensive cross-regulatory network used by the SR protein family to control their expression. Finally, we develop splice-switching antisense oligonucleotides to reverse the increased skipping of TRA2β poison exon detected in tumors, leading to selective anti-proliferative effects across a variety of cancer models. In summary, our work provides new insights into the regulatory mechanisms of SR proteins and identifies novel oncogenic spliced isoforms that represent potential biomarkers and targets for therapeutics development. Citation Format: Olga A. Anczukow. Understanding and targeting RNA splicing in breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr SY04-01.
Abstract 3987: Targeting nucleotide synthesizing enzyme dUTPase (DUT) represents a metabolic weakness and therapeutic opportunity in liver cancer
Authors: Yue Liu, Mingjing Xu, Ho Lee Wan, Alissa M. Wong, Xiaofan Ding, Kelvin K. Ng, Nathalie Wong
Journal: Cancer Research (2023)

Abstract Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, has an overall 5-year survival rate of around 20%, making it the third leading cause of cancer-related death worldwide. Upregulated nucleotide metabolism is frequently identified in HCC and represents a metabolic weakness of tumor cells. The enzyme dUTPase (DUT) catalyzes the synthesis of nucleotide precursor and prevents undesired uracil misincorporation into DNA, and thus plays an important role in the maintenance of DNA integrity and cell viability. Although common upregulation of DUT has been reported in cancers, its role in HCC remains largely unknown. In this study, we investigated the mechanism underlying DUT biology in HCC and tumor susceptibility to drug targeting dUTPase. Overexpression of DUT was found in 42% of HCC cases and significantly correlated with advanced stage tumors. CRISPR-Cas9 mediated knockout of DUT resulted in growth retardation, cell cycle arrest and a spontaneous induction of DNA damage in multiple HCC cell lines. A protective effect from oxidative stress was also demonstrated in both knockout and overexpression DUT assays. Metabolomics analysis showed altered DUT expression in HCC cells resulted in profound impact on pyrimidine and purine metabolism. In addition, levels of DUT protein strongly correlate with cellular level of dUTP and dTDP, which suggested its critical role in dNTP homeostasis. Interestingly, hepatic organoids overexpressing DUT showed drug resistance to tyrosine kinase inhibitor (TKI) Sorafenib. Both in vitro and in vivo assays confirmed that targeting dUTPase activity with TAS-114 synergized the effect of Sorafenib in suppressing HCC growth. In conclusion, our study showed that upregulated DUT conferred growth advantage to HCC cells by reducing uracil misincorporation and favoring nucleotide synthesis. Targeting DUT with its first-in-class inhibitor TAS-114 in combination with Sorafenib represents an effective treatment regime for HCC. Citation Format: Yue Liu, Mingjing Xu, Ho Lee Wan, Alissa M. Wong, Xiaofan Ding, Kelvin K. Ng, Nathalie Wong. Targeting nucleotide synthesizing enzyme dUTPase (DUT) represents a metabolic weakness and therapeutic opportunity in liver cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3987.
Abstract SY15-01: Tumor agnostic dendritic cell vaccines
Authors: Michele De Palma
Journal: Cancer Research (2023)

Abstract Dendritic cells (DCs) are specialized myeloid cells with the ability to uptake, process, and present antigens to T lymphocytes; they also generate cytokine and chemokine gradients that regulate immune cell trafficking, activation, and function. DCs pulsed with tumor antigens have been used as a platform for therapeutic vaccination in cancer. In a broadly tested clinical application called a DC vaccine, autologous monocyte-derived DCs (moDCs) are isolated from a patient with cancer, exposed to tumor antigens ex vivo (antigen loading), and matured before reinfusion to the patient. However, in spite of significant development and testing, DC vaccines based on antigen-loaded moDCs have delivered mixed clinical results. The suboptimal performance of DC vaccines may be due to the use of moDCs - a heterogenous population of non-professional antigen-presenting cells - and the artificial nature of the procedure used to "load" selected tumor antigens on moDCs ex vivo. To address both issues, we developed a DC vaccine that uses a population of mouse or human DC progenitors (DCPs) engineered to produce immunostimulatory cytokines. While not involving antigen loading, the new DC platform outperformed antigen-loaded moDCs in mouse models of cancer. Engineered DCPs produced professional cDC1 and cCD2 in mice, reprogrammed the tumor microenvironment to a form characterized by broad IFNg signaling, and inhibited tumors, including autochthonous models, in an antigen-agnostic fashion. In one application, engineered DCPs synergized with antigen-specific CAR-T cells to eradicate gliomas in mice. Citation Format: Michele De Palma. Tumor agnostic dendritic cell vaccines. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr SY15-01.
Abstract 4151: Anti-CEACAM5 immune stimulant TLR7/8 agonist antibody drug conjugate is a potent myeloid cell activator for the treatment of CEACAM5-expressing tumors
Authors: Stephanie Decary, Lydia Blot, Charlotte Lahoute, Sandrine Benoist, Anne Caron, Francesca Graziano, Marc Trombe, Loreley Calvet, Alexandra Ferrier, Marc Frederic, Sukhvinder Sidhu, Marie-Priscille Brun, Marielle Chiron
Journal: Cancer Research (2023)

Abstract Toll Like Receptor 7 and 8 (TLR7/8) agonists are a promising approach to treat tumors by harnessing the innate immune system to trigger anti-tumor innate and adaptive immunity. One of the main obstacles to the use of this class of low molecular weight molecules in cancer treatment is the toxicity associated with systemic immune activation after intravenous administration. We developed a novel immune stimulant ADC by conjugating the anti-CEACAM5 (carcinoembryonic antigen related cell adhesion molecule 5) tusamitamab antibody with a resiquimod (R848) TLR7/8 agonist payload. This tumor-targeted compound administered systemically and locally active, is expected to eradicate CEACAM5-positive (+) tumors by recruiting and activating immune cells in tumor microenvironment to promote anti-tumor immune response. Tusamitamab R848 ADC, evaluated in vitro, binds to CEACAM5+ tumor cells via its Fab moiety, and to myeloid cells via its Fc part at nanomolar (nM) concentrations. TLR7/8 pathway activation was evaluated on myeloid THP1 reporter cells. The conjugate elicits a potent and FcyR-dependent activity at low nM concentration. In co-culture of human blood cells and human CEACAM5+ gastric cancer cells, it was shown to induce phagocytosis activity, associated with increased activation/maturation of both monocytes and dendritic cells. Tusamitamab R848 ADC evaluated in vivo in CEACAM5+ pancreatic human tumor model, HPAFII, leads to robust antitumor activity with complete regressions (CR) after single administration at 5 mg/kg. In a pharmacodynamic study using lung tumor patient-derived xenograft mouse model, this ADC triggers murine cytokine inductions, innate immune cell enrollment at tumor site, and tumor necrosis in a dose-dependent manner. Based on preclinical in vitro and in vivo data, the tusamitamab R848 ADC is an innovative ADC approach with the potential to eradicate CEACAM5+ tumors in patients. Citation Format: Stephanie Decary, Lydia Blot, Charlotte Lahoute, Sandrine Benoist, Anne Caron, Francesca Graziano, Marc Trombe, Loreley Calvet, Alexandra Ferrier, Marc Frederic, Sukhvinder Sidhu, Marie-Priscille Brun, Marielle Chiron. Anti-CEACAM5 immune stimulant TLR7/8 agonist antibody drug conjugate is a potent myeloid cell activator for the treatment of CEACAM5-expressing tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4151.
Abstract 5753: RUNX3 disrupts MYC/MAX complex and promotes MYC degradation
Authors: Yoshiaki Ito, Vincent Oei, Linda Chuang, Junichi Matsuo, Supriya Srivastava, Ming Teh
Journal: Cancer Research (2023)

Abstract We reported earlier that heterozygous deletion of RUNX3 in the mouse induces adenoma in small intestine, mammary gland (1) and lung (2) and a precancerous stomach epithelium that is highly sensitive to a chemical carcinogen (3). We therefore propose that RUNX3 is a gatekeeper of cancer development (1). In our recent study on how RUNX3 inhibits early-stage cancer development in multiple tissues, we uncovered a previously unknown mode of MYC destabilization by RUNX3. From RNA sequencing, knockdown experiments, tumorigenic assays, protein interaction and ubiquitination studies, we show that the strong inhibitory effects of RUNX3 on proliferation and tumor growth may, in part, be attributed to its ability to promote MYC degradation. The evolutionarily conserved Runt domain of RUNX3 interacts directly with the basic helix-loop-helix leucine zipper of MYC, resulting in the disruption of MYC/MAX interaction, enhanced GSK3β-mediated phosphorylation of MYC protein at threonine-58 and its subsequent degradation via the ubiquitin-proteasomal pathway (4). MYC inhibitor Omomyc, a short peptide comprising the b HLH LZ domain of MYC with 4 amino acid substitutions, is extremely effective in disrupting MYC/MAX interaction (5). RUNX3 appears to function similarly to Omomyc: is RUNX3 a Nature-designed Omomyc? References:(1) Ito K et al, Cancer Cell 14;226-237, 2008; (2) Lee YS et al, Cancer Cell 24: 603-616, 2013; (3) Ito K et al, Gastroenterol 140:1536-1546, 2011; (4) Oei V, Chuang LSH, et al, Submitted; (5) Soucek et al, Nature 455:679-683, 2008 Citation Format: Yoshiaki Ito, Vincent Oei, Linda Chuang, Junichi Matsuo, Supriya Srivastava, Ming Teh. RUNX3 disrupts MYC/MAX complex and promotes MYC degradation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5753.
Abstract 986: A BioPharma best practices framework to enable successful morphology guided spatial biology studies using NanoString GeoMx® Digital Spatial Profiler
Authors: Leslie Abad, Maxine McClain, Edward Bonnevie, Benjamin Chen, Sarah Church, Gokhan Demirkan, Premi Haynes, Kelly Hunter, Anil Kersarwani, David Krull, Yan Liang, Prithwish Pal, Corinne Ramos, Deniliz Rodriguez, Jessica Runyon, Julien Tessier, Esperanza Anguiano
Journal: Cancer Research (2023)

Abstract The interest and utility of high-plex spatial profiling of RNA and protein biomarkers has increased over the last few years. The implementation of high-plex analyte spatial platforms, such as GeoMx® Digital Spatial Profiler (DSP), is increasing within discovery and development approaches for biomarkers associated with clinical outcome. The surge in spatial platforms parallels the increase of digital pathology in translational and clinical research studies. The integration of these two workflows has the potential to benefit diagnostic and therapeutic development. This study aims to facilitate the implementation of DSP in tissue analysis workflows helping those involved in drug discovery and development efforts to (1) assess platform feasibility for their research, (2) design effective DSP experiments, and (3) enable generation of high-quality, usable spatial data from large cohort studies. The BioPharma GeoMx DSP Consortium has developed consensus-based best practices incorporating the expertise of panel members via virtual meetings. Best practices guidelines for spatial profiling of tissue biopsies in drug discovery and development using GeoMx stands to advance current standard practices in tissue analysis. These best practices recommendations encompass every step of the implementation of DSP in standard tissue analysis workflows, emphasizing the importance of multidisciplinary stakeholder involvement, testing, defining experimental conditions prior to execution of large-scale studies, and considerations in assessing assay performance. This study offers a practical reference for the optimal implementation of GeoMx DSP in exploratory sample analysis for drug discovery and development studies. Citation Format: Leslie Abad, Maxine McClain, Edward Bonnevie, Benjamin Chen, Sarah Church, Gokhan Demirkan, Premi Haynes, Kelly Hunter, Anil Kersarwani, David Krull, Yan Liang, Prithwish Pal, Corinne Ramos, Deniliz Rodriguez, Jessica Runyon, Julien Tessier, Esperanza Anguiano. A BioPharma best practices framework to enable successful morphology guided spatial biology studies using NanoString GeoMx® Digital Spatial Profiler [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 986.